Dietary nitrate supplementation and cognitive health: the nitric oxide-dependent neurovascular coupling hypothesis.

Diet is currently recognized as a major modifiable agent of human health. In particular, dietary nitrate has been increasingly explored as a strategy to modulate different physiological mechanisms with demonstrated benefits in multiple organs, including gastrointestinal, cardiovascular, metabolic, and endocrine systems. An intriguing exception in this scenario has been the brain, for which the evidence of the nitrate benefits remains controversial. Upon consumption, nitrate can undergo sequential reduction reactions in vivo to produce nitric oxide (•NO), a ubiquitous paracrine messenger that supports multiple physiological events such as vasodilation and neuromodulation. In the brain, •NO plays a key role in neurovascular coupling, a fine process associated with the dynamic regulation of cerebral blood flow matching the metabolic needs of neurons and crucial for sustaining brain function. Neurovascular coupling dysregulation has been associated with neurodegeneration and cognitive dysfunction during different pathological conditions and aging. We discuss the potential biological action of nitrate on brain health, concerning the molecular mechanisms underpinning this association, particularly via modulation of •NO-dependent neurovascular coupling. The impact of nitrate supplementation on cognitive performance was scrutinized through preclinical and clinical data, suggesting that intervention length and the health condition of the participants are determinants of the outcome. Also, it stresses the need for multimodal quantitative studies relating cellular and mechanistic approaches to function coupled with behavior clinical outputs to understand whether a mechanistic relationship between dietary nitrate and cognitive health is operative in the brain. If proven, it supports the exciting hypothesis of cognitive enhancement via diet.

The Challenging Management of Acute Thrombotic Microangiopathy in Pregnancy.

Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury. Pregnancy-associated thrombotic microangiopathy is a severe disorder with a high risk of maternal mortality and poor fetal outcomes. Preeclampsia/eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome are the most common causes, and hemolytic uremic syndrome or thrombotic thrombocytopenic purpura are rare causes. Due to overlapping clinical findings, the differential diagnosis is challenging and should be managed by a multidisciplinary team. We present a case of a 38-year-old woman at 40 weeks of second gestation, admitted with thrombotic microangiopathy being the final diagnosis not immediately clear.

Reducing the viral load of SARS-CoV-2 in the saliva of patients with COVID-19.

OBJECTIVE: To evaluate the reduction in the salivary viral load using oral antiseptic mouthwashes in patients testing positive for COVID-19. METHODS: Sixty-three individuals were recruited after testing positive for COVID-19 by real-time RT-PCR assay and divided into 5 groups. Group 1 received sterile water, group 2 received 1.5% hydrogen peroxide solution (HP), group 3 received 0.12% chlorhexidine (CHX), group 4 received 0.1% sodium hypochlorite solution (NaClO), and group 5 received sequential rinses using CHX and HP. After collecting the initial saliva sample, individuals were asked to use the designated mouthwash for 1 min. Additional saliva samples were collected immediately after rinsing, 15, and 30 min after rinsing. Real-time RT-PCR assays for RNA detection of SARS-CoV-2 were performed on the saliva samples. RESULTS: There were no significant differences among the experimental groups and the control group in any period. Compared to the baseline values, there was a significant reduction in the number of copies of SARS-CoV-2 after 30 min in group 2 and immediately after the initial mouthwash in group 4. CONCLUSIONS: No experimental group demonstrated a significant reduction in the viral load compared to the control group.

Morphological alterations in tongue epithelial cells infected by SARS-CoV-2: A case-control study.

OBJECTIVE: The aim of the present case-control study was to evaluate the morphological aspects of the epithelial cells from the dorsum of the tongue and the expression of the SARS-CoV-2 Spike protein in these cells, in patients with and without COVID-19 infection. METHODS: 24 individuals with at least one symptom of COVID-19 were recruited among inpatients from Hospital Universitário Pedro Ernesto (Rio de Janeiro, Brazil). 14 patients who tested positive for COVID-19 by RT-PCR were included in the case group, and 10 patients who tested negative were included in the control group. Cytological smears from the dorsum of the tongue were obtained from all patients and analyzed using immunohistochemistry directed against SARS-CoV-2-Spike protein. Morphological changes in epithelial cells were analyzed using light microscopy. RESULTS: Immunohistochemistry showed that 71% of the COVID-19 patients presented epithelial cells positive for the presence of the SARS-CoV-2 Spike protein, and all cells coming from patients in the control group were negative. Cytological analysis showed significant differences when comparing epithelial cells from COVID-19-positive and COVID-19-negative patients. CONCLUSION: COVID-19 may generate dimensional changes in tongue epithelial cells; however, further studies are necessary to understand how this happens.

Cryptococcal dissemination to the central nervous system requires the vacuolar calcium transporter Pmc1.

Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading causes of death in HIV/AIDS patients. In order to access the central nervous system, C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood-brain barrier. In this study, we demonstrate that the calcium transporter Pmc1 enables C. neoformans to penetrate the central nervous system, because the pmc1 null mutant failed to infect and to survive within the brain parenchyma in a murine systemic infection model. To investigate potential alterations in transmigration pathways in these mutants, global expression profiling of the pmc1 mutant strain was undertaken, and genes associated with urease, the Ca2+ -calcineurin pathway, and capsule assembly were identified as being differentially expressed. Also, a decrease in urease activity was observed in the calcium transporter null mutants. Finally, we demonstrate that the transcription factor Crz1 regulates urease activity and that the Ca2+ -calcineurin signalling pathway positively controls the transcription of calcium transporter genes and factors related to transmigration.

What about adolescents' mental health after the pandemics? An analyses of a grade II hospital.

OBJECTIVES: Suicidal ideation and suicide are serious situations that affect children and adolescents. The restrictions imposed by the SARS-CoV-2 pandemic have had a significant negative impact, due to social isolation, prolonged screen exposure and reduced outdoor activities. This study aims to compare the access to the Pediatric Emergency Department due to suicidal ideation and suicide attempts before and during the pandemic. METHODS: This descriptive and retrospective study analyzed clinical records of children/adolescents who attended a Level II Pediatric Emergency Department of a hospital due to suicidal ideation and/or suicide attempts, between March 2018 and March 2020 (pre-pandemic period) and April 2020 to March 2022 (pandemic period). Demographic (age and sex) and clinical (psychopharmacological therapy, discharge destination and follow-up psychiatric/psychological consultations) variables were collected. Statistical analysis was performed using Microsoft Excel 2022® and SPSS v20.0®, considering statistical significance at p<0.05. RESULTS: A total of 71 children/adolescents were admitted for suicidal ideation, with a median age of 15 years (minimum: 10 years, maximum: 17 years), 27 in pre-pandemic period and 44 in pandemic period (p<0.001). The majority were girls, with a significant increase in pandemic period (pre-pandemic: 55.6 %, pandemic: 79.6 %; p<0.05). The age group with the highest increase in admissions was 15 years. There was a significant increase in suicidal attempts among girls (p<0.05) as well as self-harm behaviors (p<0.01). There was also a significant increase in the number of psychology/child psychiatry follow-up consultations in pandemic period (p<0.05). Most patients were referred to another hospital in both periods (pre-pandemic: 55.6 %, pandemic: 68.2 %) at discharge. CONCLUSIONS: During the pandemic period, there was an increase in the number of suicidal ideation cases, particularly among females, as well as in suicide attempts cases, which appears to be correlated with the pandemic restrictions. Larger-scale studies are needed to draw more accurate conclusions.

Musculoskeletal Morphology and Joint Flexibility-Associated Functional Characteristics across Three Time Points during the Menstrual Cycle in Female Contemporary Dancers.

Findings are inconsistent with regards to whether menstrual cycle phase-associated changes in physical functioning exist. It is possible that such discrepancies are due to varying rigour in experimental approaches. The current study aimed to systematically evaluate any effect of carefully tracked menstrual cycle phase on precisely measured muscle structure and function in a physically active group (contemporary dancers). Eleven women aged (M [SD]) 23.5 [2.94] years, undergoing 10.5 [1.73] hours of contemporary dance practice and 6.12 [2.36] hours of other physical activity per week, were recruited. Sex hormone level (enzyme-linked immunosorbent assays (ELISA), skin temperature and ovulation kits), physical pain assessments (Ice Water Test, Visual Analogue Scale, The Physical Activity Readiness Questionnaire, Self-Estimated Functional Inability Because of Pain Questionnaire, and Pain Anxiety Symptoms Scale), muscle architecture measurement (B-mode ultrasonography), and physical functioning (dynamometry, force-platform and electromyography) on both lower limbs were measured at three time points during one cycle, following three months of menstrual cycle monitoring. There was no difference in musculoskeletal flexibility variables between follicular, ovulatory, or luteal phases. Nonetheless, oestrogen change was associated with variability in 11 musculoskeletal variables, progesterone change was associated with variability in 7, and relaxin change was associated with variability in 15. Negative correlations existed between progesterone and flexibility and between oestrogen and jump variables. Moreover, oestrogen and relaxin were associated with increased musculoskeletal compliance, whilst progesterone was associated with increased muscle stiffness. In short, in absolute sex hormone levels, 'inter-individual' variances appear more impactful than 'intra-individual' variances. Not only are oestrogen and progesterone associated with differing musculoskeletal outcomes, but relaxin is also associated with musculoskeletal compliance changes. These effects are anticipated to impact jump height and flexibility, and hence, they could be expected to affect overall physical performance, including dance.

Co-segregation of trichorhinophalangeal syndrome with a t(8;13)(q23.3;q21.31) familial translocation that appears to increase TRPS1 gene expression.

Trichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant syndrome caused by haploinsufficiency of TRPS1 due to point mutations or deletions. Here, we report the first familial TRPS I due to a t(8;13)(q23.3;q21.31) translocation breakpoint <100 kb from the 5' end of TRPS1. Based on the additional abnormalities observed exclusively in the index patient that are mainly compatible with clinical features of TRPS, her phenotype was defined as expanded TRPS I including brain malformations and intellectual disability. Initial analyses did not reveal any genetic defect affecting TRPS1 or any genomic alteration within the breakpoint regions or elsewhere in the genome. The pathogenic chromosome 8q23.3 breakpoint is at position g.116,768,309_116,768,310 within a transposon type I element, 87 kb from the TRPS1 5' end. The 13q21.31 breakpoint is within a tandem repeat region at position g.65,101,509_65,101,510 (genome assembly GRCh37/hg19). This breakpoint is flanked by protocadherin 9 (PCDH9) and protocadherin 20 (PCDH20). As an outcome of the translocation, an evolutionarily conserved non-coding VISTA enhancer element from 13q21.31 is placed within the TRPS1 5' region, 1,294 bp from the breakpoint. The increased expression of TRPS1 found by three independent methods is most probably translocation allele derived and driven by the translocated enhancer element. The index patient's expanded phenotype presumably involves the epithelial-to-mesenchymal transition pathway that may be due to TRPS1 overexpression. Together, these findings support that the reported translocation-associated phenotypes are "cis-ruption" and TRPS1 overexpression related, the latter most probably caused by the novel enhancer element in the TRPS1 5' region.

Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm essentially characterized by excessive production of platelets. Molecular pathogenesis of ET is linked in approximately half of the patients to intracellular cytokine signaling dysregulation as a result of thrombopoietin receptor or Janus kinase 2 (JAK2) mutations. However, genetic defects underlying cytokine transcription have not been associated with ET. Using molecular cytogenetics and whole-genome array analyses, we uncovered a submicroscopic deletion at 20q13.2 in a JAK2V617F-positive ET patient with an acquired complex chromosome translocation. The deletion encompassed the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene that encodes a transcription factor involved in the regulation of hematopoietic cytokines. RNA interference-mediated suppression of NFATC2 mRNA or pharmacological inhibition of NFATC2 protein with 11R-VIVIT in cultured JAK2V617F-positive SET-2 megakaryocytes increased colony stimulating factor 2 (granulocyte-macrophage) (CSF2) mRNA and promoted cell proliferation. Moreover, impairment of NFATC2-calcineurin interaction with 11R-VIVIT further reduced the transcription of the NFATC2 gene. Antibody-mediated neutralization of CSF2 cytokine in inhibitor-treated cells prevented 11R-VIVIT-induced cell proliferation, indicating that impairment of NFATC2-calcineurin interaction promotes megakaryocyte proliferation through up-regulation of CSF2 transcription. Our results suggest a model in which haplo-insufficiency of NFATC2 cooperates with activation of the JAK-STAT signaling pathway in the pathogenesis of JAK2V617F-positive ET with del(20q). These results further indicate that pathogenesis of ET may be linked to genetic defects of other transcription factor genes involved in the regulation of cytokine expression.

[Venetoclax: A New Hope for Elderly Patients with Acute Myeloid Leukemia]. / Venetoclax: Uma Nova Esperança para o Doente Idoso com Leucemia Mielóide Aguda.

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by clonal proliferation, with increased incidence with advancing age. AML with myelodysplasia-related changes (AML-MRC) represents an AML subtype with a poor prognosis and challenging treatment, particularly in elderly patients. We report the case of a 77-year-old patient diagnosed with high-risk AML-MRC, ineligible for intensive chemotherapy, with frequent need of transfusion of red cell concentrates. The authors present, to the best of their knowledge, the first patient in Portugal with AML-MRC treated with an hypomethylating agent, azacytidine, and a BCL2 inhibitor (venetoclax), and that association was essential in the treatment and overall survival, which was much higher than expected.

A leucemia mielóide aguda (LMA) é uma neoplasia hematológica caracterizada pela proliferação clonal, com incidência crescente com a idade. A LMA com alterações relacionadas com mielodisplasia (LMA-ARM) representa um subtipo de LMA com prognóstico adverso, cujo tratamento é desafiante, sobretudo nos doentes mais idosos. Descrevemos o caso de uma doente de 77 anos com o diagnóstico de LMA-ARM, de alto risco inelegível para quimioterapia intensiva, com necessidades transfusionais frequentes. Tanto quanto é do seu conhecimento, os autores apresentam o primeiro caso clínico de LMA-ARM, em Portugal, tratado com a associação do agente hipometilante, azaciditina, e o inibidor BCL2 (venetoclax), o que foi crucial para o tratamento e sobrevivência global do doente, muito além da sobrevivência esperada.

Salivary Metabolomic Analysis Reveals Amino Acid Metabolism Shift in SARS-CoV-2 Virus Activity and Post-Infection Condition.

The SARS-CoV-2 virus primarily infects salivary glands suggesting a change in the saliva metabolite profile; this shift may be used as a monitoring instrument during SARS-CoV-2 infection. The present study aims to determine the salivary metabolomic profile of patients with and post-SARS-CoV-19 infection. Patients were without (PCR-), with SARS-CoV-2 (PCR+), or post-SARS-CoV-2 infection. Unstimulated whole saliva was collected, and the 1H spectra were acquired in a 500 MHz Bruker nuclear magnetic resonance spectrometer at 25 °C. They were subjected to multivariate analysis using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), as well as univariate analysis through t-tests (SPSS 20.0, IL, USA), with a significance level of p < 0.05. A distinction was found when comparing PCR- subjects to those with SARS-CoV-2 infection. When comparing the three groups, the PLS-DA cross-validation presented satisfactory accuracy (ACC = 0.69, R2 = 0.39, Q2 = 0.08). Seventeen metabolites were found in different proportions among the groups. The results suggested the downregulation of major amino acid levels, such as alanine, glutamine, histidine, leucine, lysine, phenylalanine, and proline in the PCR+ group compared to the PCR- ones. In addition, acetate, valerate, and capronic acid were higher in PCR- patients than in PCR+. Sucrose and butyrate were higher in post-SARS-CoV-2 infection compared to PCR-. In general, a reduction in amino acids was observed in subjects with and post-SARS-CoV-2 disease. The salivary metabolomic strategy NMR-based was able to differentiate between non-infected individuals and those with acute and post-SARS-CoV-19 infection.

Interim FDG18-PET SUVmax Variation Adds Prognostic Value to Deauville 5-Point Scale in the Identification of Patients with Ultra-High-Risk Diffuse Large B Cell Lymphoma.

INTRODUCTION: Interim response evaluation by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (iPET) in diffuse large B cell lymphoma (DLBCL) could be important to rule out disease progression and has been suggested to be predictive of survival. However, treatment guidance by iPET is not yet recommended for DLBCL in clinical practice. We aimed to compare the predictive value of iPET when utilizing the visual Deauville 5-point scale (DS) and the semiquantitative variation of maximum standardized uptake value (ΔSUVmax). MATERIALS AND METHODS: We included 85 patients diagnosed with DLBCL and uniformly treated with standard protocols. iPET with DS of 1-3 and/or ΔSUVmax ≥66% was defined as negative. Univariable and multivariable Cox regression analyses were performed to determine the independent factors affecting progression free survival (PFS) or overall survival (OS) and to estimate PFS and OS. RESULTS: iPET positivity, measured by DS or ΔSUVmax, showed predictive value of disease refractoriness, improved by combining DS and ΔSUVmax. After a median follow-up of 50.1 months, iPET was an independent predictor for both PFS and OS when interpreted by DS, but only for PFS by ΔSUVmax. Combined visual and semiquantitative analysis (D4-5 & ΔSUVmax<66%) was an independent predictor of PFS and OS, and allowed to identify an ultra-high-risk subgroup of patients with very dismal outcome, increasing the discriminating capacity for iPET. CONCLUSION: Our study suggests that combined DS and ΔSUVmax in iPET assessment predicts refractory disease and distinguishes ultra-high-risk DLBCL patients with a very dismal prognosis, who may benefit from PET-guided therapy adjustment.

Multiplex CRISPR editing of wood for sustainable fiber production.

The domestication of forest trees for a more sustainable fiber bioeconomy has long been hindered by the complexity and plasticity of lignin, a biopolymer in wood that is recalcitrant to chemical and enzymatic degradation. Here, we show that multiplex CRISPR editing enables precise woody feedstock design for combinatorial improvement of lignin composition and wood properties. By assessing every possible combination of 69,123 multigenic editing strategies for 21 lignin biosynthesis genes, we deduced seven different genome editing strategies targeting the concurrent alteration of up to six genes and produced 174 edited poplar variants. CRISPR editing increased the wood carbohydrate-to-lignin ratio up to 228% that of wild type, leading to more-efficient fiber pulping. The edited wood alleviates a major fiber-production bottleneck regardless of changes in tree growth rate and could bring unprecedented operational efficiencies, bioeconomic opportunities, and environmental benefits.

Impact of the COVID-19 Pandemic on Mental Health in Childhood and Adolescence: The Reality of a Portuguese School.

Background The coronavirus disease 2019 (COVID-19) outbreak has led to social isolation, with the potential to increase depressive symptoms, even at the pediatric age. Before the COVID-19 pandemic, the rate of depressive symptoms in large youth cohorts was 12.9% worldwide. Aims This study aims to characterize the impact of the COVID-19 pandemic on the pediatric population's mental health. Materials and methods This was an observational, descriptive, and cross-sectional study conducted through the use of a questionnaire, including the Children's Depression Inventory (CDI), between April 5 and May 5, 2021. The study was conducted on children and adolescents aged 7 to 17 years old in a school in the geographical area of ​​a Portuguese grade II hospital. Incomplete data were excluded. Data were statistically analyzed using the IBM SPSS® program (version 28; IBM Corp., Armonk, NY), considering statistical significance if p<0.05. Results A total of 228 children and adolescents were included; 113 were female (49.6%). The average age of the population was 12.2 years. Fifteen point four percent (15.4%) had depressive symptoms, of which 51,9% were female. Of the children and adolescents with depressive symptoms, 5.7% had a personal history of past COVID-19 infection and 42.9% had at least one family member with a history of past COVID-19 infection. Seventeen point one percent (17.1%) had at least one family member involved in pandemic-related work. Children and adolescents who were infected with COVID-19 had more depressive symptoms than noninfected children and adolescents (p=0.013). At the same time, children and adolescents, with at least one family member with a history of past COVID-19 infection, had more depressive symptoms than children and adolescents without a family history of past COVID-19 infection (p=0.004). Children and adolescents with a family member involved in pandemic-related work had more depressive symptoms than children and adolescents without any family member involved in pandemic-related work (p=0.004). Conclusions COVID-19 infection, whether personal or familiar, has an impact on mental health, even in the pediatric age, and it is imperative to know the consequences of emotional and mental changes in this population.

Corrigendum: SVInterpreter: A Comprehensive Topologically Associated Domain Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants.

[This corrects the article DOI: 10.3389/fgene.2021.757170.].

SARS-COV-2 detection in saliva and nasopharyngeal swabs using RT-PCR was similar.

The World Health Organization has declared the widespread spread of SARS-CoV-2 and its associated disease (COVID-19) a public health emergency. The standard gold test for detecting the virus is the RT-PCR, performed from nasopharyngeal swab (NPS) samples. However, this test may be uncomfortable for the patient and requires specific training and attire from the health professional responsible for collecting the sample. Therefore, the search for alternative ways to collect samples that may be used in the diagnosis of COVID-19 is relevant. This study aimed to compare the results obtained from NPS and saliva samples. NPS and saliva samples were collected from 189 symptomatic outpatients suspected of COVID-19, who came to Piquet Carneiro Polyclinic. RNA extraction was performed using the Bio-Gene DNA/RNA Viral Extraction kit (Bioclin®). Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) reactions used the Molecular SARS-CoV-2 (E / RP) kit (Bio-Manguinhos). The results indicated that 142 showed a non-detectable result (ND), while 47 showed a detectable result (D). Among the 142 "ND", 137 (94.4%) saliva samples obtained the same result, while 5 samples (3.4%) were "D". Among the 47 "D" swab samples, 35 (74.4%) showed the same result in the saliva samples. The sensitivity of the saliva test was 0.74 and the specificity was 0.97. The positive predictive value was 0.88 while the negative predictive value was 0.92. The results showed that detection of Sars-CoV-2 using saliva samples showed high sensitivity and specificity compared to nasopharyngeal swabs.

SVInterpreter: A Comprehensive Topologically Associated Domain-Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants.

With the advent of genomic sequencing, a number of balanced and unbalanced structural variants (SVs) can be detected per individual. Mainly due to incompleteness and the scattered nature of the available annotation data of the human genome, manual interpretation of the SV's clinical significance is laborious and cumbersome. Since bioinformatic tools developed for this task are limited, a comprehensive tool to assist clinical outcome prediction of SVs is warranted. Herein, we present SVInterpreter, a free Web application, which analyzes both balanced and unbalanced SVs using topologically associated domains (TADs) as genome units. Among others, gene-associated data (as function and dosage sensitivity), phenotype similarity scores, and copy number variants (CNVs) scoring metrics are retrieved for an informed SV interpretation. For evaluation, we retrospectively applied SVInterpreter to 97 balanced (translocations and inversions) and 125 unbalanced (deletions, duplications, and insertions) previously published SVs, and 145 SVs identified from 20 clinical samples. Our results showed the ability of SVInterpreter to support the evaluation of SVs by (1) confirming more than half of the predictions of the original studies, (2) decreasing 40% of the variants of uncertain significance, and (3) indicating several potential position effect events. To our knowledge, SVInterpreter is the most comprehensive TAD-based tool to identify the possible disease-causing candidate genes and to assist prediction of the clinical outcome of SVs. SVInterpreter is available at http://dgrctools-insa.min-saude.pt/cgi-bin/SVInterpreter.py.

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome-Relevance as Complementary Prognostic Biomarkers.

Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total antioxidant status (TAS) and higher levels of peroxides, nitric oxide, peroxides/TAS, and 8-hydroxy-2-deoxyguanosine compared with controls. These patients had higher 5-mC levels and lower 5-hmC/5-mC ratio and LINE-1 methylation and increased methylation frequency of at least one methylated gene. Peroxide levels and peroxide/TAS ratio were higher in patients with methylated genes than those without methylation and negatively correlated with LINE-1 methylation and positively with 5-mC levels. The 5-hmC/5-mC ratio was significantly associated with progression to acute leukemia and peroxide/TAS ratio with overall survival. This study points to a relationship between oxidative stress and DNA methylation, two common pathogenic mechanisms involved in MDS, and suggests the relevance of 5-hmC/5-mC and peroxide/TAS ratios as complementary prognostic biomarkers.